We have been examining genes involved in the leptin signaling pathway to identify gene variants impacting body composition, with the expectation that improved understanding might help the development of precision medicine approaches for obesity (1,2). We are currently intensively studying a variant MC3R that is associated with adiposity in children and which appears to have functional significance for MC3R signal transduction. Children and adults (3) who are homozygous for two rare polymorphisms (Thr6Lys and Val81Ile) have significantly greater fat mass and leptin compared with wild type or heterozygous children. Ongoing studies attempt to understand the mechanisms by which these sequence alterations impact body weight. We have successfully bred and studied novel knock-in mice expressing the human wild type MC3R(hWT/hWT) and human double-mutant MC3R(hDM/hDM). MC3R(hDM/hDM) have greater weight and fat mass, increased energy intake and feeding efficiency, but reduced fat-free mass compared with MC3R(hWT/hWT). MC3R(hDM/hDM) mice did not have increased adipose tissue inflammatory cell infiltration or greater expression of inflammatory markers despite their greater fat mass. MC3R(hDM/hDM) bone- and adipose tissue-derived mesenchymal stem cells (MSCs) differentiated into adipocytes that accumulated more triglyceride than MC3R(hWT/hWT) MSCs. MC3R(hDM/hDM) impacted nutrient partitioning to generate increased adipose tissue that appeared metabolically healthy. These data confirmed the importance of MC3R signaling in human metabolism and suggested a previously-unrecognized role for the MC3R in adipose tissue development. Current studies are seeking to understand better the roles of MC3R in peripheral metabolism including studies of hepatic autophagy. We recently obtained a floxed Mc3r mouse, which will allow us to study tissue-specific knockouts of Mc3r. We have previously found that leptin is an important predictor of weight gain in children and identified children with hyperleptinemia and leptin receptor mutations. We have also found hyperleptinemia out of proportion with body fat mass in children with psychological loss of control (LOC) over eating. Such data suggest the importance of leptin resistance as a factor stimulating weight gain and have led to recent explorations of other syndromes associated with obesity that may cause dysregulation of leptin signaling, including WAGR (4), Bardet Biedl and Alstrom syndromes (5). Current studies are directed at understanding additional genetic, physiological, and psychological factors that place children at-risk for undue weight gain (6-14), including sleep (6-7), anxiety (8-10), weight-based teasing (11) and LOC eating (12-14). We also examined if low metabolic rate may contribute to obesity in African American children (15). Some recent initiatives have targeted insulin resistance in girls at high risk for type 2 diabetes because of obesity and a family history of diabetes (22-23). Further studies are required to determine if adolescents with moderate depression show metabolic benefits after CBT. Another series of pilot studies has tested if short bouts of activity may improve glucose tolerance in children. In children who have normal weight or overweight (16), we found that interrupting sitting resulted in a significantly lower insulin and C-peptide Area Under the Curve vs continuous sitting. Interrupting sedentary time with brief moderate-intensity walking thus improved short-term metabolic function. A new trial is currently underway testing if these acute improvements are sustained over 1 week. These studies may help lead to community studies examining if interrupting sedentary behavior is a promising prevention strategy for reducing cardiometabolic risk in children. Investigations concentrating on binge eating behaviors in children suggest that such behaviors are also associated with adiposity in children and predict future weight gain in children at-risk for overweight. Two completed protocols examined efficacy of interpersonal therapy (IPT) as a weight gain preventive strategy among children and adolescents who report binge eating behaviors versus a control health education (HE) program. Among girls with high self-reported baseline social-adjustment problems or anxiety, IPT, compared to HE, was associated with the steepest declines in BMIz (p<.001) and fat mass (p<=.03). Thus, in obesity-prone adolescent girls, IPT was associated with improvements in BMIz over 3 years among youth with high social-adjustment problems or trait anxiety. We recently found (13) that youth with remission of Loss of Control (LOC) eating at end-of-treatment had lower serum glucose, higher high-density lipoprotein cholesterol and lower triglycerides at 6-month follow-up when compared with youth with persistent LOC. Thus, reducing LOC eating in adolescent girls may have a beneficial impact on some components of the metabolic syndrome. A new study is underway to examine if retraining attentional biases away from palatable foods can help children avoid weight gain. Given the rapid increase in the prevalence of obesity, the development of treatments for obesity is urgently needed (2). We have recently initiated additional translational trials related to modulation of the leptin signaling pathway using a melanocortin agonist called setmelanotide. Preliminary data suggest that the leptin resistance of patients with the rare obesity-causing disorder Bardet Biedl syndrome may be treatable with setmelanotide. Additional studies in other disorders that may be responsive to melanocortin agonists are underway. We have also initiated a new randomized controlled study examining the use of diazoxide choline-controlled-release for the obesity of people with the Prader-Willi syndrome. Finally, we have conducted studies to examine the hypothesis that administration of colchicine can decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation (17). 40 Adults with obesity were randomized to colchicine 0.6 mg or placebo capsules twice daily for 3 months. Compared with placebo, colchicine significantly reduced C-reactive protein (P <0.005), erythrocyte sedimentation rate (P <0.01), white blood cell count (P <0.005), and absolute neutrophil count (P <0.001). Changes in homeostatic model assessment of insulin resistance (P = 0.0499), fasting insulin (P = 0.07) and glucose effectiveness (P = 0.08), suggested metabolic improvements in the colchicine versus placebo group. This pilot study found colchicine significantly improved obesity-associated inflammatory variables among adults with obesity. These results suggest a larger, adequately powered study should be conducted to determine whether colchicine improves insulin resistance and other measures of metabolic health in at-risk individuals. We hope to initiate such a trial in the coming year. Related to this study, we collaborated with the Zimmerberg laboratory to study adipose tissue biopsies obtained at baseline from adults in this trial (18). Analyses examining insulin-induced phosphorylation of Akt in adipose tissue samples have supported that adipose tissue insulin resistance occurs at the whole-cell level, rather than being a graded response. Additional studies have examined: 1). How to predict prediabetes using oral glucose tolerance testing (19), 2). Determining if free fatty acid (FFA) concentrations may be a good indicator for the fasted versus the non-fasted state in children (20). 3) Studying the effects of niacin administration on FFA and growth hormone (GH) concentrations in children with obesity (21).